Final assessment report on Eschscholzia californica Cham., herba

Transcrição

28 January 2015
EMA/HMPC/680375/2013
Committee on Herbal Medicinal Products (HMPC)
Assessment report on Eschscholzia californica Cham., herba
Based on Article 16d(1), Article 16f and Article 16h of Directive 2001/83/EC as amended (traditional
use)
Final
Herbal substance(s) (binomial scientific name of
Eschscholzia californica Cham., herba
the plant, including plant part)
Herbal preparation(s)
Powdered herbal substance
Pharmaceutical forms
Herbal preparation in solid dosage forms for oral
use
Rapporteur
O. Palomino
Assessor(s)
O. Palomino
Peer-reviewer
G. Laekeman
30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom
Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555
Send a question via our website www.ema.europa.eu/contact
An agency of the European Union
© European Medicines Agency, 2015. Reproduction is authorised provided the source is acknowledged.
Table of contents
Table of contents ................................................................................................................... 2
1. Introduction ....................................................................................................................... 4
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof .. 4
1.2. Information about products on the market in the Member States ............................... 8
1.3. Search and assessment methodology ................................................................... 10
2. Data on medicinal use ...................................................................................................... 11
2.1. Information on period of medicinal use in the European Union ................................. 11
2.2. Information on traditional/current indications and specified substances/preparations .. 11
2.3. Specified strength/posology/route of administration/duration of use for relevant
preparations and indications ....................................................................................... 14
3. Non-Clinical Data ............................................................................................................. 14
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal
preparation(s) and relevant constituents thereof ........................................................... 14
3.1.1. Primary pharmacodynamics .............................................................................. 15
3.1.2. Secondary pharmacodynamic ............................................................................ 17
3.1.3. Safety pharmacology ....................................................................................... 17
3.1.4. Pharmacodynamic interactions .......................................................................... 17
3.1.5. Conclusions .................................................................................................... 17
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal
preparation(s) and relevant constituents thereof ........................................................... 18
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal
preparation(s) and constituents thereof ....................................................................... 18
3.3.1. Single dose toxicity .......................................................................................... 18
3.3.2. Repeated dose toxicity ..................................................................................... 18
3.3.3. Genotoxicity ................................................................................................... 18
3.3.4. Carcinogenicity................................................................................................ 19
3.3.5. Reproductive and developmental toxicity ............................................................ 19
3.3.6. Local tolerance ................................................................................................ 19
3.3.7. Other special studies ........................................................................................ 19
3.4. Overall conclusions on non-clinical data ................................................................ 19
4. Clinical Data ..................................................................................................................... 19
4.1. Clinical Pharmacology ......................................................................................... 19
4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s)
including data on relevant constituents ........................................................................ 19
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s)
including data on relevant constituents ........................................................................ 19
4.2. Clinical Efficacy .................................................................................................. 20
4.2.1. Dose response studies...................................................................................... 20
4.2.2. Clinical studies (case studies and clinical trials) ................................................... 20
4.3. Clinical studies in special populations (e.g. elderly and children) .............................. 21
4.4. Overall conclusions on clinical pharmacology and efficacy ........................................ 21
5. Clinical Safety/Pharmacovigilance ................................................................................... 21
5.1. Overview of toxicological/safety data from clinical trials in humans ........................... 22
5.2. Patient exposure ................................................................................................ 22
EMA/HMPC/680375/2013
Page 2/23
5.3. Adverse events, serious adverse events and deaths ................................................ 22
5.4. Laboratory findings ............................................................................................. 22
5.5. Safety in special populations and situations ........................................................... 22
5.6. Overall conclusions on clinical safety ..................................................................... 22
6. Overall conclusions .......................................................................................................... 22
Annex .................................................................................................................................. 23
EMA/HMPC/680375/2013
Page 3/23
1. Introduction
1.1. Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
•
Herbal substance(s)
Eschscholzia californica Cham. is a component part of the French Pharmacopoeia. The following
monograph exists:
-
Eschscholzia californica Cham., French Pharmacopoeia, 10th ed. (Fr. Ph. Jan 1996): Dried
flowering aerial parts of Eschscholzia californica Cham. Content: not less than 0.50 per cent
and not more than 1.20 per cent of total alkaloids, expressed as californidine (C20H20NO4+; MT
338.4) (dried herbal substance).
-
Eschscholzia (poudre d’), French Pharmacopoeia, 10th ed. (Fr. Ph. Jan 1996): Dried and
powdered flowering aerial parts of Eschscholzia californica Cham. Content: not less than 0.50
per cent and not more than 1.20 per cent of total alkaloids, expressed as californidine
(C20H20NO4+; MT 338.4) (dried herbal substance).
Eschscholzia californica Cham. (Fam. Papaveraceae) is a perennial and annual plant growing
approximately 30 cm high with alternately branching glaucous blue-green foliage. The leaves are
ternately divided into round, lobed segments. The flowers are solitary on long stems, silky-textured,
with four petals, each petal 2–6 cm long and broad; their colour ranges from yellow to orange. The
petals close at night or in cold, windy weather and open again the following morning, although they
may remain closed in cloudy weather. The plant is prolific, with numerous black or dark brown
coloured seeds held in the centre of the flower within slender, ribbed single celled seed capsules (3-9
cm long) (Bruneton, 1998).
Both aerial parts and roots contain alkaloids, the latter being richer than the former (up to 1.6%
alkaloids) (Fleurentin et al., 1996).
Synonyms: California poppy
Constituents (Bartram, 1995; Bruneton, 1998; 1999; Cheney, 1963; Felter and Lloyd, 1898 in
Mills and Bone, 2000; Fleurentin et al., 1996; Greunwald et al., 2004 ; Klvana et al., 2006;
Mills and Bone, 2005; Vogel et al., 2010):
Alkaloids: 0.50-1.20 per cent of total alkaloids, expressed as californidine; six different groups of
alkaloids have been described.
EMA/HMPC/680375/2013
Page 4/23
Pavin alkaloids in the aerial parts (most abundant and characteristic of this genus):
Aporphine alkaloids: laurotetamine and N-methyl laurotetamine are present in the whole plant,
glaucine can be found within the aerial parts (Fleurentin et al., 1996):
EMA/HMPC/680375/2013
Page 5/23
Protopine alkaloids: protopine, cryptopine and α-cryptopine are found in the whole plant, leaves and
stem (Fleurentin et al., 1996):
Benzo-phenanthridin alkaloids: Chelirubine, chelidonine and homochelidonine are present in the whole
plant, chelilutine can be found in aerial parts:
EMA/HMPC/680375/2013
Page 6/23
The group of benzo-C-phenanthridin alkaloids, and mainly sanguinarine and chelerythrine, are present
in very low quantities in aerial parts (Fleurentin et al., 1996), but are more abundant in the roots.
According to Guédon et al. (1990), the total alkaloid content in the aerial parts is close to the
minimum amount cited in the Pharmacopoeia monograph:
Alkaloid
N-methyllaurotetanina
Protopine
Allocryptopine
Eschscholzine
Californidine
Sanguinarine
Chelerythrine
Total content
Aerial parts content
(µg/ml)
0.050
0.035
< 0.001
0.103
0.350
0.015
0.005
0.558
Percentage
8.9%
6.27%
0.18%
18.49%
65%
2.6%
0.89%
100%
The presence of quaternary benzophenanthridine alkaloids (sanguinarine and chelerythrine) is
controversial. Colombo and Tomé (1991) identified both alkaloids in aerial parts of California poppy,
but these results came from an experimental culture in controlled conditions under continuous light: no
quantitative data were given. So these results could not reflect the real content of these alkaloids in
natural growing plants.
Others: Flowers contain rutin and a purple-red pigment eschscholtz-xanthin (Duke, 2001).
•
Combinations of herbal substance(s) and/or herbal preparation(s) including a description of
vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products
assessed, where applicable.
Not applicable.
EMA/HMPC/680375/2013
Page 7/23
1.2. Information about products on the market in the Member States
France: Traditional use
1.
Powdered herbal substance
2.
Dry extract, solvent water (DER: 4-6:1)
Since when on the market?
Pharmaceutical form
Posology/daily dosage
1. 1982
Hard capsules
Adults: 2 capsules twice daily (1200
mg), up to 5 capsules, if necessary
Adolescents > 12 years: 1 capsule
twice daily
1 hard capsule contains 300 mg
powder with 0.8% eschscholzine
2. 1996
Hard capsules
Adults and children > 6 years: 2
capsules twice daily
1 hard capsule contains 200 mg
extract
Indications:
1 and 2: Traditionally used in the symptomatic treatment of neurotonic conditions of adults and
children, notably in cases of mild disorders of sleep.
Spain: Traditional use
1. Powdered herbal substance
Since when on the market?
pharmaceutical form
Posology/daily dosage
1. 1982
Hard capsules
2 capsules twice daily (960 mg)
Indications:
1)
Traditional herbal medicinal product to relieve nervousness and anxiety.
2)
Traditional herbal medicinal product to improve sleep quality.
EMA/HMPC/680375/2013
Page 8/23
Regulatory status overview
Member State
Austria
Regulatory Status
MA
TRAD
Comments
Other TRAD
Other Specify:
No products in the
market
Belgium
MA
TRAD
Other TRAD
Other Specify:
No products in the
market
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
No information available
Cyprus
MA
TRAD
Other TRAD
Other Specify:
Czech Republic
MA
TRAD
Other TRAD
Other Specify:
No products in the
market
Denmark
MA
TRAD
Other TRAD
Other Specify:
No products in the
market
Estonia
MA
TRAD
Other TRAD
Other Specify:
No products in the
market
Finland
MA
TRAD
Other TRAD
Other Specify:
No products in the
market
France
MA
TRAD
Other TRAD
Other Specify:
Germany
MA
TRAD
Other TRAD
Other Specify:
No products in the
market
Greece
MA
TRAD
Other TRAD
Other Specify:
No products in the
market
Hungary
MA
TRAD
Other TRAD
Other Specify:
Iceland
MA
TRAD
Other TRAD
Other Specify:
Ireland
MA
TRAD
Other TRAD
Other Specify:
Italy
MA
TRAD
Other TRAD
Other Specify:
No products in the
market
Latvia
MA
TRAD
Other TRAD
Other Specify:
Combination products
Liechtenstein
MA
TRAD
Other TRAD
Other Specify:
Lithuania
MA
TRAD
Other TRAD
Other Specify:
Luxemburg
MA
TRAD
Other TRAD
Other Specify:
Malta
MA
TRAD
Other TRAD
Other Specify:
EMA/HMPC/680375/2013
Page 9/23
Member State
Regulatory Status
The Netherlands
MA
TRAD
Comments
Other TRAD
Other Specify:
No products in the
market
Norway
MA
TRAD
Other TRAD
Other Specify:
Poland
MA
TRAD
Other TRAD
Other Specify:
No products in the
market
Portugal
MA
TRAD
Other TRAD
Other Specify:
Romania
MA
TRAD
Other TRAD
Other Specify:
No products in the
market
Slovak Republic
MA
TRAD
Other TRAD
Other Specify:
Slovenia
MA
TRAD
Other TRAD
Other Specify:
Spain
MA
TRAD
Other TRAD
Other Specify:
Sweden
MA
TRAD
Other TRAD
Other Specify:
United Kingdom
MA
TRAD
Other TRAD
Other Specify:
No products in the
market
MA: Marketing Authorisation
TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the
products in the MSs concerned.
1.3. Search and assessment methodology
Available literature on Eschscholzia californica in the electronic databases PubMed, Toxline and The
Cochraine Library was used for a literature search. Articles were filtered by using the following terms:
Eschscholzia californica, California poppy. No restrictions to language were applied. The search was
performed twice: March 2012 and July 2013. References provided by interested parties upon the call
for scientific data were also considered.
Results in PubMed
Search term “Eschscholzia californica”: 93 references were obtained in 2013.
Search term “California poppy”: 113 results.
Results in Toxline
Search term “Eschscholzia californica”: 11 references.
Search term “California poppy”: 2 results.
EMA/HMPC/680375/2013
Page 10/23
The Cochrane Library
No references were obtained for both search terms (Eschscholzia californica and California poppy).
Toxicity data for alkaloids from Eschscholzia californica
Toxnet (http://toxnet.nlm.nih.gov/ ):
Search term “protopine”: 5 results.
Search term “cryptopine”: 1 result.
Search term “chelidonine”: 7 results.
Search term “d-glaucine”: 6 results.
Only articles found to be relevant for assessment are included in the list of references.
2. Data on medicinal use
2.1. Information on period of medicinal use in the European Union
According to the information provided by the National Competent Authorities, no preparations within
Eschscholzia californica Cham., herb with a “well-established use” can be found in the European Union.
Based on the data provided by the National Competent Authorities, some Eschscholzia californica herb
products have a “traditional use”.
Powdered dry herb
This herbal preparation is recognised as a traditional herbal preparation in several monographs and
handbooks and can be found in the European market since 1982, so traditional use in Europe is
proven.
2.2. Information on traditional/current indications and specified
substances/preparations
California poppy is a traditional medicinal plant of the American Indian population, nowadays being
used for its mild analgesic and sedative properties (and as the state flower of California) (Baldacci,
1990; Bocek, 1984; Mills and Bone, 2000) without the dangers of opiates (Felter and Lloyd,
1898 in Mills and Bone, 2000).
This species is native to California (USA) and North of Mexico and has perfectly been adapted to
several European countries where it is frequently cultivated in ornamental gardens. It is traditionally
used by the rural population of western USA as analgesic and sedative (Fleurentin, 1993).
EMA/HMPC/680375/2013
Page 11/23
California poppy is traditionally known as a soporific remedy which is harmless (Baldacci, 1990;
Bocek, 1984) and considered to be an excellent soporific, particularly for children suffering from
whooping cough; for adults it was prescribed as an antineuralgicum possessing hypnotic, anodyne and
analgesic properties.
The monograph from the Commission E (Blumenthal et al., 1998) describes the following
pharmacological properties: reduction in spontaneous motility and prolongation of pentobarbitalinduced sleep (in mice) as well as prevention of spasms induced by BaCl2 (isolated jejunum).
Combinations of California poppy herb with other components (valerian root, St. John’s wort,
passionflower herb, lemon balm leaf and others) are traditionally used for several disorders such as
“Reactive, agitated and masked depressions, melancholy, neurasthenia, neuropathy, organ neurosis,
vegetative-dystonic disturbances, imbalances, constitutional lability of the nervous system”, as well as
a sleep-inductor and sedative tea. This monograph also indicates that it should be avoided during
pregnancy due to its pharmacological activity and the lack of experiments pertaining to the use in this
period.
According to the Handbook of Medicinal Herbs (Duke, 2001), California poppy is reported to be
analgesic, anodyne, diaphoretic, diuretic, soporific and spasmolytic, the alkaloids present in the roots
are said to have feeble narcotic and respiratory effects.
Also the Encyclopedia of Herbal Medicine (Bartram, 1995) includes similar therapeutic uses:
insomnia, migraine, stressful conditions, nervous bowel, anxiety, depression, neuralgia. It combines
well with passionflower for hyperactivity and sleeplessness.
The Avis aux fabricants concernant les demandes d’autorisation de mise sur le marché de
spécialités pharmaceutiques a base de plantes (Cahiers de L’Agence N°3, Ministry of Health
and Family, France,
1998) includes the therapeutic indication « traditionally used in the
symptomatic treatment of neurotonic disturbances in adults and children, mainly for minor sleep
disorders » for Eschscholzia californica.
The reference in the Pharmacognosie. Phytochimie. Plantes médicinales handbook (Bruneton,
1998) for Eschscholzia californica lists the following traditional use: symptomatic treatment of
neurotonic disturbances in adults and children, mainly for minor sleep disorders. It is frequently used
in association with other plants such as passionflower herb or valerian root.
The monograph included in the PDR for Herbal Medicines (Gruenwald et al., 2004) describes the
internal use of preparations of the herbal substance in the treatment of insomnia, aches, nervous
agitation, enuresis nocturna in children, diseases of the bladder and liver, reactive agitative and
masked depressions, melancholia, neurasthenia, neuropathy, organic neuroses, vegetative-dystonic
disorders, mood swings, weather sensitivity, vasomotor dysfunctions, vegetative-endocrine syndrome,
constitutional weakness of the nervous system, and vasomotor cephalgia. The tea is used as a
sedative. Also its homeopathic use to treat insomnia is cited. Not to be used during pregnancy.
A recent review on Plant-based medicines for anxiety disorders (Sarris et al., 2013) includes
Eschscholzia californica as a plant with preclinical evidence of anxiolytic activity.
Mills and Bone (2005), in The Essential Guide to Herbal Safety list the traditional use of
California poppy in Western herbal medicine to reduce pain and to assist sleep. Indications include
insomnia, neuralgia, anxiety, stress migraine and nervous bowel. No contraindications are included,
except for lactation without professional advice. It was used by the women of the tribes Mendocino,
Pomo, Yuki and Kashaya to decrease and stop milk production by rubbing the mashed seed pods on
the mother’s breast (Adams and Garcia, 2006).
EMA/HMPC/680375/2013
Page 12/23
The Canadian monograph (2008) lists two medicinal uses for California poppy aerial parts:
traditionally used as a mild sedative and/or sleep aid (hypnotic) and traditionally used as an analgesic
(Mills and Bone, 2005; Hoffmann, 2003; Felter and Lloyd, 1988, in Mills and Bone, 2000). Use
during pregnancy is contraindicated.
According to the Adverse Effects of Herbal Drugs handbook (De Smet et al., 1993), aerial parts
are permitted for oral use, although use during pregnancy should be avoided, as the major alkaloid
cryptopine showed a stimulating effect on guinea pig uterus in vitro.
In Belgium, the use of aerial parts of California poppy is allowed with no dose restrictions, under the
Food Supplements national legislation since 1997 (Royal Decree of 29 August 1997, 21st
November 1997).
EMA/HMPC/680375/2013
Page 13/23
2.3. Specified strength/posology/route of administration/duration of use
for relevant preparations and indications
See section 1.2.
Traditional use
Strength (name)
Posology
Route of
administration/duration of use
300 mg powdered
Adults: 2 capsules 2 times daily. Up to 5
dry herb
capsules, if necessary
Oral administration
Adolescents > 12 years: 1 capsule 2 times
daily
Indication: Traditionally used in the
symptomatic treatment of neurotonic
conditions of adults and children, notably in
cases of mild disorders of sleep
240 mg powdered
dry herb
Adults
Oral administration / 4 weeks
Indication 1): 2 capsules 2 times daily
(breakfast and dinner)
Indication 2): 2 capsules 2 times daily
(dinner and before sleep time)
3. Non-Clinical Data
Many studies have demonstrated the in vivo and in vitro pharmacological activity of Eschscholzia
californica herba. Those studies with relevance for the clinical efficacy are included.
3.1. Overview of available pharmacological data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
The main components in Eschscholzia californica herba are isoquinoline alkaloids (such as californidine
and eschscholzine) that are responsible for the sedative, anxiolytic and minor analgesic effects
observed (Bruneton, 1998; Cheney, 1963; Fleurentin et al., 1996; Mills and Bone, 2005).
Isolated californidine has sleep-inducing, sedative, anxiolytic and spasmolytic effects (Gruenwald et
al., 2004-PDR).
EMA/HMPC/680375/2013
Page 14/23
3.1.1. Primary pharmacodynamics
In vitro studies
Aqueous-alcoholic extracts from Eschscholzia californica inhibited the enzymatic degradation of
catecholamines as well as the synthesis of adrenaline, dopamine beta-hydroxylase and monoamine
oxidase (Mills and Bone, 2000).
A 70% ethanol extract of California poppy is able to bind the 5-HT(1A) and 5-HT(7) receptors at 100
µg/ml. The main alkaloids in this extract were californidine, escholzine, N-methyllaurotanine,
caryachine and O-methylcaryachine, along with a new pavine alkaloid, 6S,12S-neocaryachine-7-Omethyl ether N-metho salt (Gafner et al., 2006).
In vivo studies
The intraperitoneal administration of the aqueous extract of the plant at 25 mg/kg in mice exerted an
anxiolytic action, as proved by changes in behavioural parameters; at higher levels, the effect became
more sedative (Mills and Bone, 2000).
A study performed by Rolland et al., (1991) intended to validate the traditional sedative indications
of Eschscholzia californica by pharmacological investigations. Thus, several doses of the aqueous
extract from aerial parts of the plant (from 25 to 400 mg/kg) were tested to determine the possible
sedative and/or anxiolytic effects on the behaviour of mice subjected to several experimental
situations. Naive male mice (Swiss) weighing 30-35 g were used for behavioural tests (two
compartments test, sleep induction test, staircase test) while naive male and female Swiss mice were
used for acute toxicity determination.
With respect to the first experiment, Eschscholzia californica induced a dose-dependent decrease of the
number of rearing and the total locomotion from the dose of 100 mg/kg while the novelty preference
was significantly affected only from 200mg/kg. ED50 was estimated to be 151 mg/kg for the locomotion
reduction and 108 mg/kg for the rearing reduction.
In the second study, California poppy aqueous extract induced a dose-dependent sleep induction from
the dose of 100 mg/kg. The sleeping induction ED50 was estimated to be 106 mg/kg. In the same
conditions, dipotassium clorazepate as the reference compound, induced significantly and dosedependent sleep in mice from the dose of 5 mg/kg (50% of sleeping mice). The results obtained after
the exposition of mice to the staircase test demonstrated that Eschscholzia californica significantly
decreased the number of steps climbed and the number of rearings affected by mice, from 200 mg/kg
(at lower dose of 25 mg/kg, the effects were reversed). ED50 was estimated to be 254 mg/kg for the
rearings and 153 mg/kg for the steps climbed; data obtained for the reference compound, dipotassium
clorazepate, were a sedative ED50 of 13 mg/kg and 23 mg/kg for the rearings and the steps climbed,
respectively. Also Eschscholzia californica significantly increased the time spent by mice in the lit box
at the dose of 25 mg/kg.
The authors concluded that the anxiolytic and sedative effects exerted by Eschscholzia californica were
proven and that these results validated the traditional therapeutic indication of this specie (Rolland et
al., 1991).
The same research group evaluated the benzodiazepine, neuroleptic, antidepressant, antihistaminic
and analgesic properties of an aqueous alcohol extract of Eschscholzia californica (Rolland et al.,
2001). The plant extract did not protect mice against the convulsing effects of pentylenetetrazol, and
did not cause muscle relaxation but appeared to possess an affinity for the benzodiazepine receptor:
thus, flumazenil, an antagonist of these receptors, suppressed the sedative and anxiolytic effects of the
EMA/HMPC/680375/2013
Page 15/23
extract. The Ec extract induced peripheral analgesic effects in mice but did not possess antidepressant,
neuroleptic or antihistaminic effects. The authors concluded that the anxiolytic and sedative effects of
Eschscholzia californica were caused by affinity for GABA receptors, as showed by suppression of
anxiolytic and sedative effects following pre-treatment with flumazenil.
Table 1 summarizes the pharmacological studies with Eschscholzia californica or any of its components.
Table 1. Summary of the pharmacodynamic studies
Author
Design
Tested product
Dose
Effect
Result
Gafner et al.,
2006
in vitro
70 % ethanol
extract of
Eschscholzia
californica
100 μg/ml
Binding to 5HT(1A) and 5HT(7) receptors
at 100 μg/ml
Not specified
Rolland et al.,
2001
Mice,
rats
Aqueous-alcohol
extract of
Eschscholzia
californica
200 mg/kg
800 mg/kg
Affinity for the
benzodiazepine
receptors
Kleber et al.,
1995
Not
specified
Aqueous-alcoholic
extracts from
Eschscholzia
californica
Not specified
Rey et al.,
1991
Not
specified
Not specified
Rolland et al,
1991
Mice
Californine and
protopine/
Aqueous alcoholic
preparation of
Eschscholzia
Aqueous extract of
Eschscholzia
californica
Inhibition of the
enzymatic
degradation of
catecholamines
as well as
synthesis of
adrenaline
Sedative and
spasmolytic
effects
Sedative and
anxiolytic
effect, induction
of peripheral
analgesic
effects
Sedative,
antidepressive
and hypnotic
activities
100 mg/kg
(familiar
environment)
200 mg/kg
Sedative
properties
25 mg/kg
Determination
of both
alkaloids by
HPLC
Sleeping
induction at
doses above
100 mg/kg
Anxiolytic action
Vincieri et al.,
1988
Not
specified
Eschscholzia
Not specified
Not specified
Hypnotic and
spasmolytic
effect
Kardos et al.,
1986
Rat
Protopine,
cryptopine,
allocrytopine
No information
Enhance 3Hgammaaminobutyric acid
(3H-GABA)
binding to brain
synaptic
receptors
Benzodiazepinelike activity
EMA/HMPC/680375/2013
Page 16/23
3.1.2. Secondary pharmacodynamic
In vitro studies
The isolated alkaloid chelerythrine was reported to be a protein-kinase C inhibitor with antitumor
activity that caused significant reduction of nociceptive responses in one study, attenuated the
development of morphine dependence and showed potent antinflammatory activity (Mills and Bone,
2000).
Chelerythrine and sanguinarine exhibited affinity for rat liver vasopressin V1 receptors and were shown
to be competitive inhibitors of [3H]-vasopressin binding (Mills and Bone, 2000).
The isoquinoline alkaloids hennemanine and norsanguinarine were isolated from a methanolic extract
of the whole plant of Eschscholzia californica and checked for their antifungal activity against
phytopathogenic fungi Alternaria melongenae, Alternaria brassicola, Alternaria brassicae, Curvularia
lunata,
Curvularia
maculans,
Helminthosporium
pennisetti,
Helminthosporium
oryzae,
Helminthosporium turcium, Fusarium undum and Fusarium lini. Hunnemanine exhibited 100%
inhibition of spore germination of A. brassicae, H. pennisetti and F. lini at 1000 ppm, whereas
norsanguinarine exhibited 100% inhibition of A. brassicola and C. maculans at this concentration
(Singh et al., 2009).
In vivo studies
No data available.
3.1.3. Safety pharmacology
No data available.
3.1.4. Pharmacodynamic interactions
No data available.
3.1.5. Conclusions
Pharmacodynamic studies have been performed with Eschscholzia californica herba or some isolated
compounds. The observed anxiolytic and sedative effects after in vitro and in vivo tests were related to
its affinity for GABA receptors and were in accordance with the traditional use of this species.
There is no information available on the safety and pharmacodynamic interactions of Eschscholzia
californica herba.
EMA/HMPC/680375/2013
Page 17/23
3.2. Overview of available pharmacokinetic data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
No data are available related to California poppy.
Only some data related to the metabolism of the isolated alkaloids californine and protopine have been
published (Paul and Maurer, 2003; Paul et al., 2004). Both alkaloids underwent hepatic
metabolism through the cytochrome P450 (CYP). Californine is metabolised by N-demethylation and/or
single or double demethylenation by CYP3A2 and CYP2D1-CYP2C11, respectively; this was followed by
catechol-O-methylation of one of the hydroxyl groups. Protopine underwent demethylenation of the
2,3-methylenedioxy group followed by catechol-O-methylation, but not N-demethylation of the former.
All phenolic hydroxyl metabolites were partially conjugated and detected in human urine (Paul and
Maurer, 2003).
3.3. Overview of available toxicological data regarding the herbal
substance(s)/herbal preparation(s) and constituents thereof
3.3.1. Single dose toxicity
The administration of the aqueous or 60% hydroalcoholic extract of the plant at doses of 5000
mg/kg/i.p. to mice did not cause any mortality (Fleurentin et al., 1996).
Powdered plant (aerial parts) did not cause any toxicological reaction after acute or subacute toxicity
studies in rat (oral administration of 300-900 mg/kg and 2000 mg/kg for 4 weeks) (Fleurentin et al.,
1996).
The aqueous extract of Eschscholzia californica did not induce the mortality up to the dose of 8 mg/kg
after i.p. and per os administration. Animals did not show any toxic manifestation on the studied
parameters. The evolution of body weight was normal, despite a small decrease in the first four hours
when eyes were closed, this effect corresponding to the sedative activity (Rolland et al., 1991).
Toxicological assessment of California poppy is hampered by the lack of relevant toxicity studies
performed by the herbal preparations or by the individual alkaloids. There are relatively old rodent LD50
studies from 1950’s to 1983 on alkaloids present in aerial parts of California poppy, i.e. protopine,
cryptopine, chelidonine and d-glaucine indicating moderate to low toxicity, values in excess of 100
mg/kg bw after peritoneal, oral, or subcutaneous administration and <100 mg/kg after intravenous
administration. The value of these studies in risk assessment is negligible. However, the observation
that the acute and subacute toxicity studies with aqueous or hydroalcoholic extracts, demonstrating no
toxicological effects at high doses (up to 2000 mg/kg for 4 weeks), suggests a certain degree of safety
in agreement with a long-term traditional use of California poppy extracts (Kelentey, 1960).
3.3.2. Repeated dose toxicity
No data available.
3.3.3. Genotoxicity
No data available.
EMA/HMPC/680375/2013
Page 18/23
3.3.4. Carcinogenicity
No data available.
3.3.5. Reproductive and developmental toxicity
No data on reproductive and developmental toxicity are available from the literature.
3.3.6. Local tolerance
No data are available from the literature.
3.3.7. Other special studies
Not available.
3.4. Overall conclusions on non-clinical data
The scientific information available on the pharmacological activity of Eschscholzia californica, herba
supports the traditional use.
Nearly 85% of the alkaloid content in California poppy corresponds to pavine alkaloids (californidine
and eschscholzine), with unknown toxicity. Toxicity data for the other isolated alkaloids indicate a low
toxicity: taking into account the low percentage of these compounds in Eschscholzia californica aerial
parts, toxicity in humans, when taken at the recommended doses, is not expected. There might be
possible effects of other constituents of the plant on the absorption of the active principles, but no
further details are available.
These data are in accordance with the traditional use of the plant, which can be found in the European
market for more than 30 years without any safety concern.
Non-clinical information on the safety of Eschscholzia californica herba is scarce. As there is no
information on reproductive and developmental toxicity the use during pregnancy and lactation cannot
be recommended. Due to the lack of genotoxicity studies, a list entry cannot be recommended.
4. Clinical Data
4.1. Clinical Pharmacology
4.1.1. Overview of pharmacodynamic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
No data available.
4.1.2. Overview of pharmacokinetic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
No data available.
EMA/HMPC/680375/2013
Page 19/23
4.2. Clinical Efficacy
Only a few clinical studies have been published with Eschscholzia californica herba. The most relevant
data are summarized in this section..
4.2.1. Dose response studies
No data available.
4.2.2. Clinical studies (case studies and clinical trials)
An open study including 60 patiens (2 children, 38 women, 20 men) suffering from sleep disorders and
treated with California popy has been published. Adults received 2 g of one marketed product with E.
californica as a nebulizer (2 capsules of 0.50 g at dinner and before sleep time), while children
received a total dose of 0.5 g. Treatment duration was 6 months. After this period, 43% patients
reported excellent results, mainly for sleep quality; 43% patients reported good results, while 14%
gave up the study because of the lack of efficacy. Authors concluded that E. californica exerts a
positive, effective and constant action on sleep disorders (Baldacci, 1984).
Only two clinical trials have been reported with the aim of studying the efficacy of Eschscholzia
californica in anxiety disorders. a) The main objective was to assess the clinical efficacy of a neurotonic
component containing fixed quantities of two plant extracts (Crataegus oxyacantha and Eschscholzia
californica) and magnesium versus placebo in mild-to-moderate anxiety disorders with associated
functional disturbances: 75 mg of dry hydro-alcoholic extract of the flowering head of Crataegus
oxyacantha, 20 mg of dry aqueous extract of Eschscholzia californica and 75 mg of elemental
magnesium (i.e. 124.35 mg of heavy magnesium oxide) (Hanus et al., 2004). A total of 264 patients
(81% female; mean age: 44.6 years) presenting with generalised anxiety (DSM-III-R) of mild-tomoderate intensity (total Hamilton anxiety scale score between 16 and 28) were included in a doubleblind, randomised, placebo-controlled trial. Patients were randomly assigned to two groups: 130
received the study drug and 134 received a placebo (two tablets twice daily for 3 months). Efficacy and
safety data were recorded before first administration and 7, 14, 30, 60 and 90 days after start of
treatment.
With respect to the main outcome measures, efficacy was assessed by (a) change in Hamilton anxiety
scale total and somatic scores; (b) change in patient self-assessment; (c) number and percentage of
responsive subjects (reduction of at least 50% in Hamilton or self-assessment score); and (d) the
physician's clinical global impression. Tolerance was assessed by undesirable events spontaneously
reported by the patients over the study period. Results showed a Total and somatic Hamilton scale
scores and subjective patient-rated anxiety fell during treatment, indicating clinical improvement. The
decrease was greater in the study drug than in the placebo group. End of treatment clinical
improvement, as measured by the mean difference between final and pre-treatment scores, was, for
the study drug and placebo groups: -10.6 and -8.9 on the total anxiety score, respectively (p =
0.005); -6.5 and -5.7 on the somatic score, respectively (p = 0.054); and -38.5 and -29.2 for
subjectively assessed anxiety, respectively (p = 0.005). The risk/benefit ratio as judged by the
investigating physicians was also significantly better in the study drug than in the placebo group. In all,
15 patients (11.5%) in the study drug group and 13 patients (9.7%) in the placebo group experienced
22 and 15 adverse events, respectively. Undesirable events were mainly mild or moderate digestive or
psychopathological disorders.
EMA/HMPC/680375/2013
Page 20/23
Authors concluded that the preparation containing fixed quantities of Crataegus oxyacantha,
Eschscholzia californica, and magnesium proved safe and more effective than placebo in treating mildto-moderate anxiety disorders (Hanus et al., 2004).
b) One product containing 3 grams of the dried herb standardized to 0.8% isoquinoline alkaloids
(californidine, escholtzine and protopine) is authorised by Health Canada and marketed as an analgesic
and mild sedative (hypnotic) to be used as an analgesic or co-analgesic in the management of chronic
pain (Chamberland, 2012).
This open-label trial was carried out in order to obtain analgesic proof-of-concept and preliminary
safety and efficacy information on the product. Two studies were performed: a 7-day and 30-day study
with ten patients per study. A total of 20 men and women between 18 to 80 years of age with chronic
pain were enrolled into the study. Three clinics participated in the trial. The product was administered
either once a day or twice a day and daily for up to 1 month. Subjects were excluded from the study if:
they were allergic to California poppy; if there was clinical evidence for severe renal/liver/pulmonary,
neurologic,
cardiovascular,
metabolic,
haematological,
or
psychiatric
condition
which
in
the
Investigator’s opinion contraindicated treatment with California poppy; if the subject had heart or liver
disease or was taking heart medication; had taken an investigational drug (i.e., participated in a
pharmaceutical drug clinical trial) within 30 days prior to screening; was pregnant or breastfeeding.
The efficacy was measured using patient questionnaires at baseline and during an interim and final
visit after 1 month of treatment . The short form of the McGill Pain scale was used to record the degree
of severity of pain as measured by the Pain Visual Analog Outcome Scale. A questionnaire was used to
record insomnia. Adverse events and concomitant medication were recorded.
The authors concluded, that the standardized extract of California poppy can be used in the
management of chronic pain and as a hypnotic-mild-sedative for the management of pain-related
insomnia. It can be used as a co-analgesic in combination with other pain medications to help reduce
the intensity/severity of pain to a tolerable level (dosage: 1 capsule BID). It was well tolerated in
combination with the majority of other pain medications; insomnia (excitation) and urticaria were the
only observed adverse events. The data also demonstrated that the studied product can be used as an
analgesic-hypnotic in cases of mild-to-moderate night pain (dosage: 1 capsule at bedtime, according
the Health Canada monograph for California poppy).
4.3. Clinical studies in special populations (e.g. elderly and children)
Not found.
4.4. Overall conclusions on clinical pharmacology and efficacy
The existing data do not meet the criteria for "well established medicinal use" in accordance with
Directive 2001/83/EC. The plausibilitiy of efficacy of the medicinal product is only based on longstanding use and experience and allows the development of a European Union herbal monograph on
the traditional use of Eschscholzia californica herba.
5. Clinical Safety/Pharmacovigilance
No data available.
EMA/HMPC/680375/2013
Page 21/23
5.1. Overview of toxicological/safety data from clinical trials in humans
No data available
5.2. Patient exposure
No data available
5.3. Adverse events, serious adverse events and deaths
No data available
5.4. Laboratory findings
No data available
5.5. Safety in special populations and situations
No data available on: use in children and adolescent; contraindications; special warnings and
precautions for use; drug interactions and other forms of interactions; fertility, pregnancy and
lactation; overdose; effects on ability to drive or operate machinery or impairment of mental ability;
safety in other special situations.
5.6. Overall conclusions on clinical safety
No data available
6. Overall conclusions
Well-established use can not be accepted for Eschscholzia californica Cham., herba, due to the lack of
data on clinical efficacy, in accordance with Directive 2001/83/EC.
There exist no data in relation to reproductive and developmental safety, therefore, the use of
California poppy in pregnancy is not recommended. Also, because of the lack of data on genotoxicity, a
list entry is not suggested.
Some data related to the toxicity of some isolated alkaloids from E. californica have been published.
Most of the studies were performed more than 40 years ago and do not fulfil the current guidelines for
toxicity studies. Moreover, the obtained data for every isolated compound demonstrate a very low
toxicity risk after oral intake. Safety of California poppy has been investigated and because of the longstanding use, no major safety concerns can be derived in relation to the use of E. californica in the
recommended posology and conditions of use.
The traditional medicinal use of Eschscholzia californica Cham., herba, is well documented in several
handbooks throughout a period of at least 30 years (15 years in the European Union) under Directive
2001/83/EC as powdered substance. A traditional use as soporific, sleep-inducing, analgesic and
sedative has been described for Eschscholzia californica Cham., herba. The long-standing use has
shown that Eschscholzia californica, herba can be recognized as safe when used in recommended
dosages under the conditions specified in the monograph.
EMA/HMPC/680375/2013
Page 22/23
In conclusion, a monograph Eschscholzia californica Cham., herba, for oral use is recommended with
the following indications:
1) Traditional herbal medicinal product for relief of mild symptoms of mental stress.
2) Traditional herbal medicinal product to aid sleep.
Annex
List of references
EMA/HMPC/680375/2013
Page 23/23

Final assessment report on Eschscholzia californica Cham., herba

Transcrição

Documentos relacionados

1-Close to You

SING OUT – Repertoire Trauungen

Unser Repertoire für Trauungen

LITERARY KNOWLEDGE AND THE STEREOTYPING OF LEGAL

Reading 23

Aloe monograph - European Medicines Agency

community herbal monograph on psyllium seed

Draft assessment report on Chelidonium majus L., herba

wb compagnie GmbH Dr.-Georg-Schaefer

Devo estar falando Português?